Hyponatremia is the most common electrolyte disorder of hospitalized patients in the United States, and represents a significant cause of morbidity and mortality in this country. Although clinical studies have provided important insights into the pathogenesis of hyponatremia, considerable debate still exists concerning the incidence of morbidity and mortality from hyponatremia itself, and even more so concerning the cause of the demyelinative disease of pontine and extrapontine myelinolysis which sometimes follows correction of hyponatremia. Because controlled clinical trials would be very difficult in this patient population, studies using an appropriate animal model which nimics the clinical features of hyponatremia in human patients provide a timely opportunity to better understand the physiology and pathophysiology of hypoosmolar disorders in human patients. This competing renewal application utilizes the model o chronic stable hyponatremia developed in rats during the initial period of funding of this grant to further study the physiological processes involved in both adaptation to hyponatremia and deadaptation following correction of hyponatremia. Studies proposed in this application will extend our knowledge of the physiological changes accompanying adaptation to an deadaptation from hyponatremia by organic osmolytes to determine the studies will provide the theoretical basis for then evaluating several alternative methodologies for correcting chronic severe hyponatremia in rats in an attempt to decrease the frequency of osmotic demyelination following rapid correction of hyponatremia, which may potentially lead to future clinical trials of analogous treatment methods in human hyponatremic patients to allow more rapid corrections of hyponatremia while minimizing the risk of subsequent demyelination. In addition, the neurophysiological basis of other neurological complications of hyponatremia will be studied intensively using this model, including an evaluation of the cause and duration of the well-known increased incidence of seizures in actively hyponatremic patients, and studies of the degree to which hyponatremia impairs survival of magnocellular vasopressin and oxytocin neurons following pituitary stalk injury. The combined studies in this proposal will therefore address several important clinical questions about the physiology and pathophysiology of hypoosmolar disorders which cannot be adequately investigated via clinical studies. They will evaluate several potential alternative therapies for correcting hyponatremia that could not be evaluated in humans, and may have significant clinical implications with reqard to how patients with hyponatremic seizures and head trauma should be optimally treated. Because the data collected to date using this animal model demonstrate that it reproduces most of the clinical features of human hyponatremia caused by the syndrome of inappropriate ADH secretion, these studies will be directly relevant to the pathophysiology and therapy of hyponatremic conditions in human patients as well.